The overall hypothesis is that insulinotropic peptides from the and somatostatin-28 [S-28], a "decretin", act in concert to modulate insulin secretion on during absorption and assimilation of nutrients. Specific questions include: 1) Do "ineretine" and S-28 differentially alter the periodicity and threshold of glucose-mediated insulin secretion in vitro and in vivo? 2) Do S-28 and "incretins" module periodicity and kinetice of insulin secretion during nutrient absorption and is there a hierarchal order of importance amongst the putative "ineretins"? 3) Do elevated levels of S-28, contribute to defective insulin secretion in diabetes sellitue? The hypothesis is based on emerging information that enteric peptides including secretion, CCK, GIP and GLP-1 (7-36) potentiate the release of insulin, whereas, S-28 also from the gut, way inhibit insulin secretion. From pancreatic islet models, insulin appears to be released at varying glucose threabolds and it is plausible that "incretins" and S-28 may shift the threshold and rate of insulin release by glucose and also alter the periodicity and/or amplitude of its cyclic release. Since glucone-mediated first-phase insulin secretion [equated with threshold sensitivity] is deficient in Type II diabetes mellitus, it is possible that S-28 may adversely shift the sensitivity threshold in this disorder. To address these questions, we will evaluate the effects of secretion, CCK, GIP and GLP-1 (7-36) and S-28, separately and together, on the threshold and rate of insulin release in the perfused rat pancreas and in man. Periodicity and amplitude of insulin release will also be used. To evaluate the "physiologic" role of "incretine" and S-28 in modulating insulin secretion in vivo, baboons will be studied before and after immunoneutralization of circulating "incretins" and S-28, separately and together, during nutrient intake. To evaluate the role of S-28 on insulin secretion in defective B-cells, baboons, treated with small doses of streptozocin to induce early changes in insulin secretion, and the Goto rat model of Type II diabetes mellitus vill be examined. Insulin secretion before and after immunoneutralization with S-28 monoclonal antibodies during nutrient absorption will be tested. The results of these experiments should provide a more comprehensive view of the physiologic importance of the entero-insular axis in modulating insulin secretion.